CELLS OF TH2 CYTOKINE PHENOTYPE PREVENT LPS-INDUCED LETHALITY DURING MURINE GRAFT-VERSUS-HOST REACTION - REGULATION OF CYTOKINES AND CD8+ LYMPHOID ENGRAFTMENT

A murine parent-into-F1 graft-vs-host reaction (GVHR) model that utili zes LPS to induce lethality was used to evaluate the in vivo regulator y role of donor cells of Th2 cytokine phenotype. Transfer of B6 spleen cells into B6C3F1 hosts was lethal when LPS endotoxin (15 mug) was ad ministered on day 7 after cell transfer. Parental cells of Th2 cytokin e phenotype were generated by treating B6 mice in vivo with a combinat ion of IL-2 and IL-4 or with high dose IL-2. The CD4-enriched populati on from these cytokine-treated mice expressed and secreted increased l evels of IL-4 and IL-10, with concomitantly decreased IL-2 and IFN-gam ma. Cell mixing experiments (parental spleen cells + parental CD4-enri ched, Th2-type cells) demonstrated that the Th2-type cells protected F 1 hosts from LPS-induced lethality. These mice were analyzed to study possible mechanisms by which this protection was mediated. Compared wi th mice undergoing LPS-induced lethality during GVHR, Th2-protected mi ce had: 1) lower levels of donor CD8+ lymphoid engraftment, 2) in vivo suppression of IFN-gamma mRNA, 3) in vivo augmentation of IL-4 mRNA, and 4) a reduction in serum TNF-alpha. We thus conclude that donor cel ls of Th2 cytokine phenotype prevent LPS-induced, TNF-a-mediated letha lity during GVHR, and that this protection is associated with regulati on of both cellular- and cytokine-mediated events. As a result, we pro pose that cells of Th2 cytokine phenotype may represent a novel approa ch for establishing allogeneic lymphoid engraftment without lethal gra ft-vs-host disease.